Percutaneous transluminal coronary angioplasty has been operated to treat coronary-stenosing diseases such as arteriosclerosis and the like. The angioplasty was first performed in human body by Gruenzig et al. in 1977 and it has been firmly established as a curative method for treating coronary diseases. Presently, 500,000 people per year have been reported to be treated with the method worldwidely (Holmes, D. R. et al., Am. J. Cardiol., 53: 77C-81C, 1984). In Korea, the angioplasty has also been performed actively, especially at the university hospitals.
Since operational apparatuses for the percutaneous transluminal coronary angioplasty were developed diversely, the angioplasty has been widely performed so as to be applied to various diseases. Practically, the angioplasty has been operated in single vessel disease and multiple vessel disease, stable angina pectoris and instable angina pectoris, acute myocardial infarction and the like (Nobuyoshi, M. et al., J. Am. Coll. Cardiol., 17: 198B, 1991; Waller, B. F. et al., J. Am. Coll. Cardiol., 17: 58B-70B, 1991).
Although the angioplasty treated by using the balloon dilatation catheter, etc. succeeded clinically at the rate of 95%, acute closure and restenosis can be induced before and after the operations.
The restenosis described above may be induced by the mechanisms such as the vascular remodeling, the abnormal proliferation of the injured smooth muscle cell (SMC), the formation of extracellular matrix and the like (Wither, H. R. et al., Cancer, 34: 39-47, 1974; Thames, H. D. et al., Int. J. Radiat. Onco. Biol. Phys., 7: 1591-1597, 1981).
Although the smooth muscle cell within the vessel is not proliferative normally, physical defects and stimuli incite smooth muscle cell to migrate into the inner layer of blood vessel, to multiply or to form a matrix tissue.
In the early days of coronary angioplasty, such a restenosis would occur in approximately 30-45% of treated patients. New methods such as atherectomy, rotabulation, use of transluminal extraction catheter (TEC), excimer laser coronary angioplasty and inserting stents made of metallic wire (1) as shown in FIG. 1 have been accomplished in order to reduce the restenosis rate.
The above methods were also performed by using anti-thrombocyte agent, anti-coagulant, steroids, calcium channel blocker, colchicine and the like coincidently in order to prevent the restenosis. But effective drugs reducing the restenosis has not been discovered yet. Recently, local drug delivery and gene therapy are prevailing and they show good effects in in vitro study, but the effects shown in in vivo study are not certain. The uncertainty of effects of such treatment results from the blood flow washing off the above drugs in the blood vessel. Therefore it is difficult to administer the drugs in the blood vessel and especially in specific sites of the vessel.
However, no operation has been reported to reduce the induction rate of the restenosis outstandingly except the insertion of stents which expands and supports the restenosed sites.
Regarding the treatment of esophageal cancer, the esophagus site which is stenosed due to cancer cell proliferation should be enlarged physically to enable the patients to eat food and therefore prolong life. Although the stent is also utilized for the treatment as described above, the general metallic stent is in adequate for reducing the restenosis. Since the stent could not prevent the restenosis efficiently and the cancer cell penetrates through the struts of the stent, the inner cavity of the esophagus gets narrowed. In order to solve such problems, thin cylindrical tube (sleeve-type) made of polyethylene and the like has been developed to surround the outside of the stent. But such a stent can not remedy the cancer sufficiently and fundamentally (U.S. Pat. No. 5,282,824).
As described above in the transluminal coronary angioplasty and the esophageal cancer treatment, the restenosis is reduced by physical inhibition of the stent implantation from vascular remodeling which contracts the blood vessel and the esophagus. At the restenosed sites, lesions of the blood vessel and the proliferation of the cancer cells also induces neointimal hyperplasia. In these cases, irradiation can prevent the cell proliferation and decrease the number of progenitor cells in the regenerating tissues.
Regarding the irradiation effects of inhibiting cell proliferation, ionizing radiation is reported to inhibit the thymidine uptake and the collagen synthesis in the cultured fibroblast and to prevent proliferative lesions or keloids generated after the surgical operation even at a low dosage. At that time, about 10 Gy (1000 rad) of fractionated irradiation may be delivered for the treatment, which does not affect the normal treatment process.
In order to effectively prevent the restenosis induced after operating the transluminal coronary angioplasty in coronary artery-stenosing diseases, the metallic stent coated with radionuclides such as Ir-192, Y-90, P-32 and the like has been utilized instead of the simple stent. Many researches on the radioactive stent have been made to prevent the restenosis fundamentally. Radiation emitted from the stents destructs the proliferating cells, and thus can be exploited to prevent the restenosis.
Hitherto, the radioactive metallic stent containing radioactive nuclides (Co-55, Co-56, Co-57, Mg-52, Fe-55) emitting gamma-ray and beta-ray has been prepared by Hehrlein et al. (Hehrlein, et al., Circulation, 88 suppl.I, 1993). The above stents were made of stainless steel (Palmaz-schatz, Johnson & Johnson International System) and bombed with protons in a cyclotron, which has been applied to rabbit iliac artery. At that time these radioactive nuclides of the stent have safety problems since the nuclides emitted gamma-rays and had a long half life. Thus pure beta-ray emitting nuclides such as P-32 has been adopted to develop the radioactive stent. Precisely, Strecker stent was reconstructed by the process which non-radioactive element P-31 was ion-implanted beneath the outer surface of the titanium wire. Resultantly the radioactive stent containing P-32 can be prepared by neutron irradiation in the nuclear reactor (Laird, J. R. et al., Circulation, 93: 529-536, 1996).
Besides, the methods for inserting the radioactive stent containing radioisotopes have been developed in order to perform the radiation therapy efficiently. The general stent is inadequate for the therapy since the radioactivity of the stent can not be controlled easily. The radioisotopes are mainly located on the surface of the coating material or in the metal alloy of the stent and the amount of the radioactivity emitted from the stent is mainly controlled by their half lives. Therefore after the insertion of the stent, the amount of the radioactivity can not be adjusted properly to the response of the patient's state. In order to settle the shortcomings, a minimally invasive medical device for providing the radiation treatment has been designed (U.S. Pat. No. 5,484,384).
Precisely, the medical device comprises an outer sheath, a wire coil and a flexible elongated member having distal and proximal portion which can slide through the sheath. The elongatable distal portion contains radioisotopes so that the device can be utilized for the radiation therapy controlling the radioactivity. And the distal portion forms a longitudinal curvature at the end of the wire coil and expands from the outer sheath so as to contact blood vessel. At that time the wire coil itself is composed of a radioactive metal alloy or is coated with radioisotopes such as Ir-192.
In addition, an invasive medical device which is combined with a sleeve containing radioisotopes dispersed onto the wire coil has been designed. In detail, the device comprises an elongatable distal portion, an expandable balloon and a catheter and can irradiate the wall of the blood vessel by expanding the wall of the balloon with radioactive liquid instead of gas (Fearnot, U.S. Pat. No. 5,484,384, 1996).
However, there are problems such as the inner cavity of the esophagus being narrowed again because tumor cells proliferates and cancer cells penetrates as shown in the previously developed stents. And the processes for coating and implanting the metallic stent is not simple. Therefore the stents have not been widely utilized clinically although many kinds of stents were developed.
Especially, radionuclides emitting beta-rays has such a short transmitting distance that it should be evenly dispersed throughout the surface of the metal wire for determining the absorption dose and the treatment dose of the radiation exactly. Besides, the space between the struts of the general stents can not be irradiated sufficiently in spite of uniform coating of the wires since most metallic stents have cylindrical shape composed of wires. It is also dangerous to use the stent since the contact region of the tissue with the metal struts may be irradiated too much.
Therefore, the present inventors have attempted to develop a radioactive stent resolving the above problems of the general metallic stent. Precisely the radioactive stent has been prepared by either covering the commercialized metallic stent with cylindrical thin sleeves made by mixing radionuclides with a carrier solution or by directly immersing the metallic stent in the above carrier solution and drying the solvents. Thus the radioactive stents prepared in the present invention were attempted to prevent the penetration of esophageal cancer cells and restenosing vascular diseases effectively.